Good morning. My name is Sarah, and I will be your conference operator today. At this time, I would like to welcome everyone to the Karyopharm Therapeutics Fourth Quarter and Full Year 2021 Financial Results Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Sarah Connors, Vice President, Corporate Communications. Please go ahead.

Thank you, Sarah, and thank you all for joining us on today's conference call to discuss the top line results from the Phase III SIENDO study as well as Karyopharm's fourth quarter and full year 2021 financial results. Today, I am joined by Mr. Richard Paulson, President and Chief Executive Officer; Ms. Sohanya Cheng, Chief Commercial Officer; Dr. Jatin Shah, Chief Medical Officer; Mr. Mike Mason, Chief Financial Officer; Mr. Stephen Mitchener, Chief Business Officer; and Sharon Shacham, Chief Scientific Officer. Earlier this morning, we issued 2 press releases, one announcing top line results from the Phase III SIENDO study in endometrial cancer and one detailing Karyopharm's financial results for the fourth quarter and full year 2021. These releases, along with the slide presentation that we plan to reference during today's call, are available under the Events and Presentations section of our website, karyopharm.com. Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on Slide 2. These include statements about our future expectations, clinical developments and regulatory matters and time lines, the potential success of our products and product candidates, including our expectations relating to the commercialization of XPOVIO and NEXPOVIO, financial projections and our plans and prospects. Actual results may differ material from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent quarterly report on Form 10-Q, which is on file with the SEC and in other filings that we may make with the SEC in the future. Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so, even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today. If you turn to Slide 3, you can see our agenda for today. I will now turn the call over to Richard. Please turn to Slide 4.

Thank you, Sarah, and good morning, everyone. As we work to defeat cancer and improve patient lives, I'm very pleased to report that the Phase III SIENDO study met its primary endpoint of a statistically significant improvement in median progression-free survival compared to placebo. Selinexor-treated patients had a median PFS of 5.7 months compared to 3.8 months for patients on placebo, representing an improvement of 50% with a hazard ratio of 0.70 and a p-value of 0.0486. Additionally, selinexor demonstrated sustained and a long-term improvement in progression-free survival. At 12 months, there was an improvement in patients in remission from 25.8% to 35.3%, representing a 37% increase in probability that selinexor-treated patients will be in remission compared to patients on no treatment or today's standard of watch and wait. In this study, selinexor was well tolerated with no new safety signals identified and a low discontinuation rate of 10.5% due to adverse events. Karyopharm will work with investigators and the FDA to complete a full evaluation of the SIENDO data. Importantly, the preliminary data also identified a prespecified subgroup, wild-type p53, known as the guardian of the genome, which achieved a statistically significant reduction in the risk of disease progression or death. In this pre-specified subgroup currently consisting of 103 patients, the data showed an almost fourfold improvement in progression-free survival for selinexor-treated patients with a median progression-free survival of 13.7 months compared to 3.7 months for patients on placebo with the hazard ratio of 0.38 and a p-value of 0.0006. We plan to submit a supplemental new drug application to the FDA during the first half of '22 and also plan to submit the detailed results from the study for presentation at upcoming medical meetings in the first half of '22. I would like to acknowledge the exceptional work…

Thank you, Richard, and good morning, everyone. As Richard mentioned, we have maintained strong growth in the fourth quarter and continue to make excellent progress across key indicators since our second-line plus launch at the beginning of 2021. Please now turn to Slide 8. On this slide, we show how we have rapidly evolved XPOVIO dosing in 3 important ways over the past 2 years to improve efficacy and the patient experience. On the left, from a high dose administered at 160 milligrams per week to lower doses of 60 to 100 milligrams. In the center, from twice weekly to once-weekly dosing and on the right, evolving from a doublet in later lines to triplets in earlier lines. While XPOVIO in combination with Velcade is the approved indication and the only indication we promote to XPOVIO in combination with pomalidomide, daratumumab and carfilzomib are also included as part of the NCCN guidelines for the treatment of second-line plus multiple myeloma. This evolution is an important part of the drug's life cycle, and we have worked rapidly to explore different doses and combinations as we continue to expand the breadth and depth of XPOVIO's life cycle. Turning now to Slide 9. It is clear that over the last few quarters, we positively changed the growth trajectory and continue to make steady progress across key indicators. We continue to see a positive shift from the penta-refractory setting towards earlier lines with the most rapid growth this year in the third line as we continue to focus our messaging on XPOVIO as a new class of therapy in the white space of second to fourth line in the myeloma treatment journey. We are also expanding in the breadth and depth of use of XPOVIO with strong growth in the community setting. We continue to add more accounts every quarter and increase penetration at top myeloma accounts. In addition, our intent to prescribe data continues to show sustained improvement in the efficacy and safety perception of the product and growing confidence in utilization in earlier lines as physicians have an increasingly positive experience with the lower dose once-weekly XPOVIO-based triplet regimen. While we continue to see the impact of COVID on oncology patient visits compared to pre-COVID baseline, our field team achieved a high level of live engagements with physicians in the fourth quarter. As we've all observed in January, the Omicron variant has added pressure on the health care system and our access to providers. We will continue to adapt to this and remain focused on strong execution and positioning XPOVIO as a standard of care in second-line plus. Building on our momentum in 2021 and with a rapidly advancing myeloma pipeline, we expect to continue to drive steady growth in the near, mid and long term. If you'll advance to Slide 10, I will now turn the call to Jatin to discuss the positive update from a Phase III SIENDO study, evaluating selinexor in patients with endometrial cancer. Jatin?

Thank you, Sohanya. First, I would like to send a thank you to our teams, the SIENDO investigators, our Lead Global Investigator and Steering Committee Chair, Dr. Vergote from the University of Leuven Cancer Institute in Belgium, and the lead U.S. principal investigator, Dr. Vicky Makker from Memorial Sloan Kettering as well as our partners, the European Network for Gynecological Oncology Trials and the GOG Foundation, and of course, the patients who participated in the SIENDO trial and their families. Now please turn to Slide 11, where I'll recap the positive SIENDO results covered by Richard. I am very pleased to report the Phase III SIENDO results demonstrate selinexor's significantly extends remission in patients with advanced or recurrent endometrial cancer. Selinexor-treated patients had a median progression-free survival of 5.7 months compared to 3.8 months for patients on placebo, representing an improvement of 50%. The hazard ratio of 0.70 with a p-value of 0.0486, representing a 30% reduction in the risk of death, disease progression or death. In addition, selinexor demonstrated sustained and long-term benefit in progression-free survival as seen at 12 months, with a 37% increase in the probability that a selinexor-treated patient will be in remission compared to patients on no treatment for today's current standard of care of watch and wait. In this study, selinexor was well tolerated with no safety signal -- no new safety signals identified and a low discontinuation rate of 10.5% due to adverse events. Additionally, the preliminary data also identified in a prespecified subgroup wild-type p53, again, known as the guardian of genome, we achieved a statistically significant reduction in the risk of disease progression or death. In this prespecified subgroup of patients with wild-type p53 currently consisting of 103 patients, the data showed an almost fourfold improvement in progression-free survival for selinexor-treated…

Thank you, Jatin. We have a meaningful market opportunity in front of us. Turning to Slide 13. While most of the 66,000 cases in the U.S. are diagnosed with early stage disease and have a good prognosis after surgery alone, approximately 14,000 patients each year in the U.S. will present with advanced or recurrent disease. Of those patients, up to 67% of those treated with chemotherapy will respond, translating to approximately 9,000 patients being eligible to benefit from selinexor in the maintenance therapy in the front line. Further driving and enhancing that opportunity are several factors: First, maintenance therapy is already well established with physicians that treat multiple solid tumors, including breast and ovarian cancer; second, progression-free survival of 5.7 months demonstrated by selinexor in SIENDO is superior to the watch-and-wait approach used today; third, patients are treated until progression in the maintenance setting; fourth, selinexor is an oral medicine that is well positioned to be the first and only treatment post chemotherapy in the maintenance setting that has the potential to extend time in response and remission; and finally, Karyopharm has an established and strong commercial and medical affairs footprint, which is rapidly engaging in preparing for a potential launch. In summary, as we turn to Slide 14, we believe selinexor has the potential to become an exciting new standard of care for women with advanced or recurrent endometrial cancer. This belief is driven by powerful Phase III results, a dire unmet need in the maintenance setting and a significant market opportunity. In short, a paradigm shift for patients living with advanced endometrial cancer. Turning to Slide 15. I'd like to now turn the call back to Jatin to discuss highlights from some of our other core programs.

Thank you, Sohanya. Turning to Slide 16, we'll now turn to our other core programs, which are focused on blood cancers. We are confident in our programs with a proven track record with robust clinical data. Selinexor has demonstrated strong response rates, both as a single agent and in combination in many hematologic indications, first in myeloma and diffuse large B-cell lymphoma and more recently, in myelofibrosis and myelodysplastic syndromes. Single-agent activity is one of the key factors in predicting positive Phase III results and regulatory approvals and selinexor has been no exception. In multiple myeloma, there is an increasing use of at least 80% and growing in the first 2 lines of an anti-CD38-based therapy. There's limited data in 1 to 4 lines of therapy from trials of how to manage patients whose disease progresses after an anti-CD38-based treatment. This is where we have focused and generated data with selinexor-based combinations that include pomalidomide, carfilzomib and bortezomib, with a goal of solving that data gap. As you can see on Slide 17, the design of our Phase III SPd study continues to fill this data gap and further evaluates and entrenches selinexor-based combinations post an anti-CD38. This study will compare the triplet regimen of elotuzumab, pomalidomide and dexamethasone, or EPd, versus SPd. This will be our global study that's expected to recruit up to 280 patients who'll receive 1 to 4 prior lines of therapy. We expect to dose the first patient during the first quarter of 2022 and top line data is expected in 2024. If approved, the SPd triplet with the second all-oral triplet combination approved in relapsed/refractory multiple myeloma. Turning now to the XPOVIO regulatory expansion beyond the U.S. on Slide 18. We continue to see increased access to selinexor worldwide through regulatory filings made by…

Thank you, Jatin. Turning now to Slide 30. Our business development activities continue to focus on leveraging strategic partners to support commercialization outside the United States. As Richard mentioned earlier, in December 2021, we signed an exclusive license agreement with the Menarini Group, whereby Menarini will develop and commercialize NEXPOVIO in the EU, the U.K. and Latin America, among other territories. In exchange, Karyopharm received an upfront payment of $75 million and is eligible to receive an additional $202.5 million in future milestones based on regulatory and sales performance, plus tiered double-digit royalties on net sales. Menarini is a strong EU-based partner with over $4 billion in annual revenue. They operate in over 140 countries and have a deep commitment to developing treatments addressing oncologic and hematologic diseases. This deal adds to the growing global footprint, bringing XPOVIO to patients worldwide with partners FORUS in Canada, Neopharm in Israel and Antengene in Asia Pacific. With Antengene, Karyopharm recorded $19.5 million in milestone revenue from Antengene in the fourth quarter 2021, with cash payment expected 1 year from the anniversary of their launch. Turning to our financials. Since we issued a press release earlier today with the full financial results, I will just focus on the highlights beginning on Slide 31. Total revenue for the fourth quarter of 2021 was $126.3 million compared to $35.1 million for the fourth quarter of 2020. Net product revenue from U.S. commercial sales of XPOVIO for the fourth quarter of 2021 was $29.8 million compared to $20.2 million for the fourth quarter of 2020, representing a 47% increase year-over-year. The estimated gross to net discount for XPOVIO in the fourth quarter was 15%. We expect gross to net discount to be in the 15% to 20% range for the full year of 2022. We recognized $96.5 million of license and other revenue in the fourth quarter of 2021, including the upfront payment of $75 million from Menarini. R&D expenses for the fourth quarter of 2021 were $44 million compared to $37.2 million for the fourth quarter of 2020. SG&A expenses for the fourth quarter of 2021 were $34.6 million compared to $33.9 million for the fourth quarter 2020. Cash, cash equivalents, restricted cash and investments as of December 31, 2021, totaled $235.6 million compared to $276.7 million as of December 31, 2020. Based on our current operating plans, we are expecting net product revenue of $135 million to $145 million for 2022, reflecting approximately 40% growth compared to 2021. Non-GAAP R&D and SG&A expenses, which excludes stock-based comp expense, to be in the range of $265 million to $280 million for the full year of 2022. And finally, our existing cash, cash equivalents and investments as well as the revenue we expect to generate from XPOVIO product sales and other license revenues will be sufficient to fund our planned operations into early 2024. I'll now flip to Slide 32 and turn the call over to Richard for some final thoughts. Richard?

Thanks, Mike. 2021 was a very strong year for Karyopharm, and I'm excited about our future, especially following the positive Phase III SIENDO study plus our progressing and focused pipeline. We are maintaining strong momentum with a number of key near-term catalysts and corporate milestones for us to deliver on as we continue to deliver for patients with high unmet needs and strengthen our organization as outlined on Slide 33. For the multi myeloma program, we expect to leverage our commercial capabilities, striving to become the standard of care in second-line plus post anti-CD38 and increase U.S. XPOVIO sales throughout the year. To dose the first patient in our Phase III study evaluating selinexor, pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma in the first quarter and receive a decision from the CHMP and EMA under MAA requesting approval for selinexor, ruxolitinib and dexamethasone in patients with multiple myeloma following at least one prior therapy in the first half of 2022. For the endometrial cancer program, we plan to submit the detailed results from the study for presentation at upcoming medical meetings in the first half of '22. We plan to submit a supplemental new drug application to the FDA during the first half of '22. And finally, we plan to conduct prelaunch activities in anticipation of a potential approval and launch in the first half of '23. For the myelofibrosis program, we expect to report top line Phase I data in combination with JAK inhibition in treatment-naive myelofibrosis during the second half of '22 and report top line Phase II data in previously treated myelofibrosis during the second half of '23. And finally, for the MDS program, we expect to report preliminary Phase I eltanexor data in combination with an HMA and frontline MDS in '22 and report top line Phase II data in HMA refractory MDS in the first half of '23. In closing, I would like to give a heartfelt thank you to our teams, especially all the dedicated people who served to move the SIENDO trial forward during COVID and deliver our data rapidly. I look forward to updating the investment community on our continued progress in the months and quarters ahead. And with that, I would now like to ask the operator to open the call up to the question-and-answer portion of today's call. Operator?

[Operator Instructions] Our first question comes from Maury Raycroft with Jefferies.

Congrats on the update today. I'll start off with myeloma guidance. Can you tell us what's going into your assumption of $145 million to $155 million and the 40% growth for XPOVIO in 2022? What proportion of earlier line patients are you assuming? And is there anything built into your assumptions on durability?

Thanks, Maury. Just to correct that, our guidance is $135 million to $145 million for the year. And maybe I'll let Sohanya talk to what's going into that guidance. Sohanya?

Great. Thanks, Maury, for the question. So yes, we feel very confident about the annual guidance of $135 million to $145 million, which is roughly 40% growth year-over-year, and it's in line with many best-in-class launches in the multiple myeloma space. As far as growth drivers, we look at what drove growth in 2021, and it was strong execution and the new positioning in the white space of second to fourth line, and we'll continue to focus in these areas. There are 3 key growth drivers. The first is the continued shift into earlier lines, where we anticipate seeing the most continued rapid growth in the third line. In fact, in 2021, XPOVIO was the fastest-growing multiple myeloma product in the third line, and we anticipate continuing to see this shift into earlier lines. We are approaching roughly about half of our patients now in the second to fourth line and then the remaining half in the fifth line plus. The second growth driver is the continued expansion in the breadth and depth of use of the product. So we continue to add more accounts as well as increase our penetration at our top myeloma accounts. The third growth driver is to continue to move the needle on our intent to prescribe data and the perception of the product. And as the community is building confidence in our use of our new lower dose once-weekly XPOVIO-based triplet regimen, that shift will continue to happen. So those are the kind of the key ingredients driving growth and part of the guidance for next year.

Got it. That's really helpful. And I also wanted to ask a question on SIENDO. So if you can talk more about the proportion of endometrial maintenance that is wild-type p53, and how does that population fit into your regulatory and commercial strategy?

Yes. Thanks so much for that, Maury. So when we look at patients with p53 wild-type, that's approximately 50% of patients with advanced endometrial cancer who have this -- and we looked within our study, approximately 50% as well in our study have wild-type p53, so consistent with what we see in the broader patient population. I think the second question comes to the regulatory kind of path forward of that. So I think I want to be very clear and remind folks that we have a positive Phase III study for the overall patient population. So we have ongoing discussions with the agency, and we'll continue to have that. So this will be part of that discussion for the final label negotiation.

Got it. And also for the 103 patients, so that number with the wild-type p53, is that a 2:1 ratio too for this study? Or can you say more about how many patients were in the treatment arm versus placebo? And just clarifying, does that number represent the number of events? Or is the PFS for the p53 population still maturing?

Yes. So those 103 patients, I would say, the final top line results are based on 104 patients and same thing for the subgroup analysis. So that itself is fixed. And so we'll present the full data set at a major medical meeting.

Our next question comes from Peter Lawson with Barclays.

Congratulations. On the SIENDO study, just as we think about the p53 subgroup, is that something you'll push in the label? Or are you going for a broader label for maintenance setting in endometrial cancer?

Yes. Thanks, Peter. I think as we just touched on, the overall study, obviously, as we've shared is positive and has a positive statistical significant improvement in patients in the maintenance setting. And so when we look at this area right now, there are no other approved therapies for these patients. So as we look at that, we need to understand the full data set as we continue to do the analysis on this, and then we'll engage with the FDA over the near term to work on reviewing the data and determining what the final label will be.

Got you. And will we get a p53 mutant breakout for whether it's PFS or hazard ratio?

Yes, absolutely. So we'll provide the full data set as we present at a major medical meeting.

Our next question comes from Mike Ulz with Morgan Stanley.

Just a follow-up on XPOVIO 2022 guidance and just thinking about the quarterly progression here. Should we consider maybe any seasonality in 1Q or continued maybe pressure from Omicron that persists in 1Q?

Sohanya, do you want to take that?

Yes. Thanks for the question, Mike. So we are not disclosing quarterly guidance. We've provided the annual guidance of $135 million to $145 million. As far as quarterly seasonality, given the variances we see in the market in the different quarters, to your point, we will focus on year-over-year performance moving forward for that quarter. And again, we feel positive about the annual guidance we've given. To answer your question on Omicron variant, so in Q4 and 2021, we did see the impact of COVID on oncology patient visits compared to pre-COVID baselines. However, in January, the Omicron variant has now added pressure on the health care system and our access to providers, but we continue to leverage a very nimble and patient-centric sales force and strong digital and commercial capabilities, and we continue to see strong [indiscernible] across our key growth drivers. So we remain laser focused on strong execution and positioning XPOVIO as a standard of care in the second-line plus.

Our next question comes from Brian Abrahams with RBC.

This is Steve on for Brian. I'm curious, do you plan to revisit any other indications in the SINE study to look for a possible effect of p53, say, in ovarian or cervical cancer? And maybe as a follow-up, were there any differences in the adverse event profile between the wild-type p53 population and the overall population?

Yes. So I'm sorry, the first question was on adverse event profile. And so I think what we can comment is that we don't expect to see any differences right in the biology between those 2 patient populations, and we'll provide that full data set as we move along. What's key though is that what you need is something that's well tolerated in the maintenance setting, and the biggest indicator is at 10.5% discontinuation rate, which is very low in that setting. It really speaks to the tolerability of once-weekly low-dose selinexor in the maintenance setting. Can you repeat your first question for me?

It was on looking at other indications in SINE -- with the SINE -- that were in the SINE study.

Yes. So looking at ovarian cancer and endometrial and cervical cancer, so those are the 2 other histologies in the SINE study, ovarian and endometrial. So we're clearly committed to gynecologic malignancies, and we'll have further discussions, but again, our 4 key programs is going to be myelofibrosis, MDS, myeloma and endometrial cancer, and we'll continue to build upon this platform.

Our next question comes from Eric Joseph with JPMorgan.

I'm curious -- as it relates to SIENDO, I'm curious whether you've taken a preliminary look at OS trend. Appreciating that it's not primary, it's going to be a secondary endpoint here. Just wondering whether it might be a gating factor to an sNDA submission and whatever OS might be part of the overall package that you would submit to FDA. And then secondly, as it relates to the primary endpoint analysis of PFS, does the statistical analysis plan make any distinction between intent to treat at a per protocol treatment population? And if so, what population is reflected in this top line data set?

Yes, absolutely. So number one, no, overall survival is not a gating factor to submission of the sNDA. Number two, It's too early with 2 few events with overall survival events to make any conclusions. And number three, for the primary PFS per the statistical analysis plan and reviewed by the FDA, it is primary -- it is progression-free survival by investigator on the intent to treat, and that's the data that we have presented.

Okay. Great. And perhaps if I could follow up, just one XPOVIO question, commercial question related to the guidance and also 4Q performance. Can you just comment on how patients that were new to brand trended in the fourth quarter compared to third quarter. And as part of the guidance for this year, how should we be thinking about that metric new to brand trending sequentially?

Thank you, Eric. Maybe I'll turn that to you, Sohanya.

Yes. Thanks, Eric. So we continue to show strong new patient starts, and we also showed improvement in our refill rates with patients staying on therapy longer because of the earlier line shift. Think as we move into 2022, those 3 key growth drivers of the earlier line shift, the increase in the breadth and depth of use and the improvement in our intent to prescribe data should all contribute towards increased momentum with our new patients as well as our refill rates.

Our next question comes from Jonathan Chang with SVB Leerink.

Congrats on SIENDO. First question, what is your strategy for commercial success in SIENDO? Are there lessons learned from the multiple myeloma and DLBCL experience that are applicable here? And second question, can you provide any color around the duration of treatment that you're seeing in multiple myeloma? And are you seeing a difference in duration between earlier line versus the [ penta-refractory ] multiple myeloma treatment setting?

Yes. Thanks, Jonathan. Maybe I'll take the first question. So I think, again, when you look at the SIENDO patient population, obviously, we're still going to be engaging very much with regards to our action and our plans forward. I think this is very different than multi myeloma because there are currently no approved therapies in the maintenance setting. So we have the potential to be the first and only therapy. We believe in this by itself is a real significant market opportunity because I think, as Sohanya talk to, is an incidence of 14,000 patients in frontline with about 67% responding to chemotherapy. So those numbers obviously are different than the multi myeloma markets in the different areas. So now in the maintenance setting, the difference here is, you're really treating through progression. And as we have shared in here in the median PFS for the total population, it's 5.7 months, but also in that p53 wild-type population at 13.7 months. We've shown through that with a discontinuation rate of 10.5%, that's really been well tolerated for those 13 months. So as we know in our study, approximately 50% of the wild-type p53 patients are in the study, and that's -- the p53 status is a very known and actionable mutation as part of the kind of standard evaluation work up for when people are looking at their patients. So as we move forward, we need to continue to do more work on this, but it's well understood, well documented, well measured. And physicians, I think if patients are really looking for moving away from the watch and wait and being able to move to treat their cancer and obviously, extend their time in remission. So very excited about it and then also kind of a very different opportunity. And then the last point I would close with on that is, in here, we're taking our established teams, which are well established, which are delivering excellent results and are going to be able to move forward rapidly and engage with health care practitioners following the potential approval and a label. And then for the second part of the question, maybe I'll turn to Sohanya to talk overall about what we're seeing in terms of evolution for patients being on therapy in multiple myeloma.

Thanks, Richard. So multiple myeloma duration therapy, so preliminary data is showing more patients are staying on therapy longer, and again, that's driven by a shift into earlier lines and better side effect management. Now it's important to remember this data is still maturing. We're still in the early stage of our second-line plus launch. So we cannot definitively guide to duration at this time. And we are also in that dynamic phase of our transition into earlier lines of use, but as we evolve into earlier lines and we are now approaching that 50-50 split between second to fourth line and fifth line plus in our patient population with our greatest growth happening in our third line, we will continue to see these patients in earlier lines stay on therapy longer.

Our next question comes from Ed White with H.C. Wainwright.

Can you discuss perhaps the use -- the prescribing under the label with Velcade versus what you're seeing with the other drugs under the NCCN guidelines? How is that breaking out? And how is the growth been under with the NCCN guidelines?

Great.

Sohanya, do you want to take that?

Yes. So XPOVIO-based triplet use as an overall trend, that is rising significantly. And to break it down, 60% or so from the data that we see of XPOVIO-based triplets are XPOVIO combination with Velcade and dex. And again, this is our approved indication and the only triplet regimen we promote to. But we also know, to your point, there are other combinations with pomalidomide, carfilzomib and daratumumab on the NCCN guidelines to those that remaining 40% or so of that triplet use from the data that we see where it's those other combinations, but an overall rapid rise in that trend from doublet to triplet.

Our next question comes from Arlinda Lee with Canaccord.

I guess I had another one on the duration. Can you comment maybe on the duration of treatment? Is that contributing on the growth in sales? Is it from improved duration versus -- what proportion can you help us understand improved duration versus new patients? And then on the SIENDO side, can you remind us when you initially started the trial, what were kind of the ongoing regulatory discussions then? And maybe what FDA was looking for and how you came about that?

Sohanya, do you want to talk to the first part?

Yes. Thanks, Arlinda. So again, the earlier line shift, right, it's got 2 drivers here. One is, there's a large addressable population in the earlier line, and hence, XPOVIO can be -- that remains a focus for us to establish in the second to fourth line setting. But in addition, the growth driver is as these patients move into earlier lines, they do stay on therapy longer. So a second-line patient will stay on therapy longer than a fourth-line patient. So preliminary data is showing that more patients are gradually staying on therapy longer, and that's driven primarily by that shift into earlier lines, but also the better side effect management. Again, data is still maturing. We're still a year into our BOSTON launch, and so we can't definitively guide to mean duration, also that we are still in that dynamic phase into the earlier line shift. But we're seeing kind of good progress as that early align shift happens with those patients staying on therapy longer.

And Jatin, maybe you can just address the second part of Arlinda's question.

Yes, absolutely. So we're engaged with the agency throughout the entire life cycle of the trial from the beginning and continuously. And the one key point from the regulatory discussions is it's clear that the primary endpoint is progression-free survival by investigator on intent to treat and that has not changed. And that's where result -- we report positive Phase III results from SIENDO.

[Operator Instructions] Our next question is a follow-up from Peter Lawson with Barclays.

Just on the wild-type p53 population, does that make you rethink in any way the use in endometrial in the sense of potential use in earlier line or combinations, et cetera?

Yes, great question. Thanks for that, Peter. Obviously, we share the same excitement around p53 as well as the entire population. We'll dive more into this with additional data analysis with our investigators and the agency for future trials.

Got you. And the -- just maybe a question on the P&L. Just what was the stock option expense in 2021? I'm just trying to back out the guidance.

Mike, do you want to manage that?

Sure. Our stock comp expense was just about $30 million.

$30 million. Perfect. And just on the p53 mutant population, are you going to break that out or just wait for a conference? And would that be -- would you have to break down the label as well for the p53 mutant population?

We'll break -- it will be broken out at a conference as the data is presented, and then I think as we said, we have to engage with the FDA and look at the totality of the data and determine the outcome, if you look at that in the label.

Got you. How should we think about pricing in the endometrial population?

It's the same, I mean our product is already on the market so it's going to be remaining at the same price. I think the key thing, again, to look at is in the maintenance setting, patients are really treating themselves to progression. So with physicians and patients, they want to extend the time in remission, and I think that's where it's really important looking at those median PFS we talked to, but also looking at [indiscernible] talk to the real importance that over that long tail. And when you're seeing that about 39% of patients are still in remission 1 year after starting therapy. I think that would be very important when you get the duration of therapy. And as we talked to, we see with the discontinuation, that's been very well tolerated for a long period of time. And for instance, the 13 months that we see in the wild-type p53 population. So all those factors, we'll obviously look at the total value of the market, but from a pricing perspective, we're at the same price we're already in the market.

Got you. Okay. And then just a final question on the guidance. I know you're not doing quarterly guidance, but are there any headwinds or tailwinds that we should be thinking about year-over-year when we're kind of doing the model?

Sohanya, do you want to take that one?

Yes. I think that the tailwinds are really the key growth drivers where we continue to sustain our momentum. As far as headwinds, I think the wild cost continues to remain the impact of Omicron variant. But as I mentioned earlier, we are adapting to it, and we've got strong commercial digital capabilities. And we'll see how that evolves, but our focus remains on strong execution and positioning XPOVIO as the standard of care in second-line plus.

This concludes our question-and-answer session. I would like to turn the conference back over to Richard Paulson for any closing remarks.

Thank you, operator, and thank you for all of our participants today in the call. With that, again, we look forward to being able to share ongoing progress as how we're moving forward with our pipeline and are working forward to continue to focus on trying to defeat cancer and benefit patients' lives for fighting cancer. So thank you very much, operator.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.